Uterine leiomyomas occur in approximately 77% of all women in the United States and can cause severe morbidity and infertility. To date, there is no effective treatment for leiomyomas aside from hysterectomies. We have previously shown that the AKT pathway is activated in the majority of fibroids and that inhibiting this pathway results in regulation of specific mechanisms that ultimately drive cells into cellular senescence or cell death. In addition, we observed that oxidative stress is upregulated in leiomyomas due in part to suboptimal growth conditions and a modification (acetylation) of the detoxifying enzyme, manganese superoxide dismutase (MnSOD) that inhibits its function. We hypothesize that reactive oxygen species (ROS) can promote growth of leiomyomas through the AKT pathway. In turn, when AKT is inhibited, ROS promotes senescence and cell death. In Aim 1, we will determine whether increased levels of ROS, through the induction of miR- 182, drive p16 and HMGA2 localization to heterochromatin foci and promote senescence. In Aim 2, we will determine whether ROS can decrease BCL2 function and expression resulting in mitochondria permeability and release of DNA damaging molecules. We will also investigate the role of ROS and AKT in a unique stem cell population in maintaining ?stemness?. Investigation of the mechanisms underlying senescence and cell death upon inactivation of AKT will not only enhance our understanding of how fibroids grow and survive, but also inform the future development of new therapies for fibroids.